This K05 Senior Scientist Award is designed to provide the applicant protected time in order to continue ongoing research on the pathology and treatment of cytokine-induced depression. Depression in the medically ill is a significant public health concern, occurring in up to 50% of patients and having a significant impact on treatment adherence, quality of life, and morbidity and mortality. New developments in the conceptualization of depression in the medically ill have focused on the potential role of immune activation/inflammation and the associated release of proinflammatory cytokines. Proinflammatory cytokines have been found to influence neurobiologic function including neurochemistry and behavior, and induce a depressive syndrome that has overlapping features with major depression. The long-term objective of the proposed work is to further understand the pathology and treatment of this cytokine-induced depression as it relates to depression in the medically ill, including patients with HIV/AIDS. As a model system, we plan to study patients receiving the cytokine, interferon (IFN) alpha, for the treatment of hepatitis C, which afflicts approximately 4 million individuals in the US and up to 25% of patients with HIV/AIDS. IFN alpha is a potent inducer of proinflammatory cytokines (especially interleukin 6) and leads to depressive symptoms in 30-50% of patients depending on the dose. In addition, IFN alpha activates corticotropin releasing hormone pathways and has been shown to lead to monoamine depletion in laboratory animals. IFN alpha also has been shown to alter fronto-striatal neurocircuitry in humans and induce REM sleep changes (decreased REM latency, increased REM percentage); changes consistent with the neurobiology of depression. Thus, IFN alpha treatment provides a unique model system to further understand the pathology and treatment of cytokine-induced mood disorders. The specific aims of the proposed research plan are 1) To determine the neuroendocrine pathways involved in the vulnerability to and development of cytokine-induced depression, 2) To determine the neural circuitry of cytokine-induced depression using functional magnetic resonance imaging and positron emission tomography, and 3) a) To test the efficacy of antidepressants in patients receiving IFN alpha therapy for hepatitis C (including patients with HCV/HIV co-infection) and b) To test novel strategies for the treatment of cytokine-induced depressive symptoms including cytokine antagonists and dopamine agonists. Results from these studies will provide important new data on neural pathways by which cytokines induce depression and will establish a foundation for developing novel strategies to diagnose and treat depression in the medically ill. In addition to the proposed research, the applicant will develop his skills in the area of neuroimaging and will participate in training and education of pre- and postdoctoral fellows and junior faculty, as well as serving as Director of the HIV/AIDS Clinical Research Training Program.